title: The RNA polymerase "switch region" is a target for inhibitors.
abstract: The alpha-pyrone antibiotic myxopyronin (Myx) inhibits bacterial RNA polymerase (RNAP). Here, through a combination of genetic, biochemical, and structural approaches, we show that Myx interacts with the RNAP "switch region"--the hinge that mediates opening and closing of the RNAP active center cleft--to prevent interaction of RNAP with promoter DNA. We define the contacts between Myx and RNAP and the effects of Myx on RNAP conformation and propose that Myx functions by interfering with opening of the RNAP active-center cleft during transcription initiation. We further show that the structurally related alpha-pyrone antibiotic corallopyronin (Cor) and the structurally unrelated macrocyclic-lactone antibiotic ripostatin (Rip) function analogously to Myx. The RNAP switch region is distant from targets of previously characterized RNAP inhibitors, and, correspondingly, Myx, Cor, and Rip do not exhibit crossresistance with previously characterized RNAP inhibitors. The RNAP switch region is an attractive target for identification of new broad-spectrum antibacterial therapeutic agents.
authors.affiliation: Howard Hughes Medical Institute, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Mukhopadhyay
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.forename: Sajida
authors.initials: S
authors.lastname: Ismail
authors.forename: David
authors.initials: D
authors.lastname: Koppstein
authors.forename: Minyoung
authors.initials: M
authors.lastname: Jang
authors.forename: Brian
authors.initials: B
authors.lastname: Hudson
authors.forename: Stefan
authors.initials: S
authors.lastname: Sarafianos
authors.forename: Steven
authors.initials: S
authors.lastname: Tuske
authors.forename: Jay
authors.initials: J
authors.lastname: Patel
authors.forename: Rolf
authors.initials: R
authors.lastname: Jansen
authors.forename: Herbert
authors.initials: H
authors.lastname: Irschik
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.forename: Richard H
authors.initials: RH
authors.lastname: Ebright
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007783:Lactones / Q000494:pharmacology; D008958:Models, Molecular; D011401:Promoter Regions, Genetic; D016963:Thermus thermophilus / Q000201:enzymology*; D014158:Transcription, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D007783:Lactones; C532894:corallopyronin A; C096600:ripostatin A; C040322:myxopyronin A; D012321:DNA-Directed RNA Polymerases